The loss of cells and profound brain atrophy in Alzheimer's disease contributes to many of the clinical features of the disease. Initial synaptic toxicity followed by overt cell death has been proposed as a mechanism (Delaere et al., Acta Neuropathol. 77.6 (1989): 645-53). Aβ peptide, the primary component of the AD plaque, has been proposed to play a role in both synaptic and overt cell toxicity. Soluble Aβ rather than plaque-associated Aβ has been reported to correlate with loss of the synaptic protein synaptophysin (Lue et al., Am. J. Pathol. 155.3 (1999): 853-62). Non fibrillar forms of Aβ have been reported to have some synaptotoxic (Wang et al., J. Neurosci. 24.13 (2004): 3370-78; Lacor et al., 24.45 (2004): 10191-200) or overt toxic effects in cultures (Kim et al., FASEB J. 17.1 (2003): 118-20).
Aβ neurotoxicity can be analyzed by a polymerization-dependent toxicity assay (Wogulis et al., J. Neurosci. 25.5 (2005): 1071-80) in which soluble and fibrillar Aβ are combined to allow aggregation. If the aggregation occurs in or on a cell membrane, robust toxicity and deposition occurs. Specific integrin heterodimers mediating deposition, overt toxicity and synaptic toxicity of Aβ effects on LTP have been reported (Wright et al., Neurobiol. Aging 28.2 (2007): 226-37; Wang et al., Neurobiol. Aging 29.10 (2008): 1485-93).
Perlecan is a heparin sulfate proteoglycan that can be subdivided into five domains. Domain V (DV) also known as endorepellin is an 85-kDa C-terminal domain of perlecan. DV consists of three laminin globular (LG) domains, each separated by two epidermal growth factor (EGF)-like domains. The C-terminal most LG domain, known as LG3, is specifically processed from full length perlecan by the BMP-1 family of tolloid metalloproteases (Gonzalez et al., J. Biol. Chem. 280.8 (2005): 7080-87) and the cysteine proteinase cathepsin L (Cailhier et al., Journal of Biological Chemistry 283.40 (2008): 27220-29), and is normally found in the human urinary, blood and cerebrospinal fluid proteomes (Pieper et al., Proteomics. 4.4 (2004): 1159-74; Adkins et al. Mol. Cell Proteomics 1.12 (2002): 947-55; Cartier et al., Scand. J. Clin. Lab Invest 64.2 (2004): 101-07). Perlecan has been reported to have a role in cell growth, differentiation, brain and cardiovascular development, and inflammation (Bix & Iozzo, Microsc. Res. Tech. 71.5 (2008): 339-48). Domain V and LG3, a proteolytic fragment, have been reported to inhibit angiogenesis in endothelial cells in vitro and in vivo via direct interaction with the ligand-binding domain (I domain) of α2 integrin, (Bix et al., J. Cell. Biol. 166.1 (2004): 97-109; Bix et al., J. Natl. Cancer Inst. 98.22 (2006): 1634-46, U.S. Pat. No. 6,821,947). Perlecan has also been proposed to have a role in wound healing (see U.S. Pat. No. 7,488,719). A perlecan fragment consisting of residue 3464-3707 of the human sequence has been reported to occur in body fluids of multiple sclerosis patients (U.S. Pat. No. 7,510,843). DV has also been reported to enhance binding of collagen to α2 β1 integrin (Bix et al., Blood 109.9 (2007): 3745-48).